Problem: Over the last two decades, unintentional opioid-related overdose has emerged as a major public health threat in the United States. This increasingly common, yet preventable, cause of morbidity and death among users of prescription opioids is partially due to a substantial expansion in the prescription of opioid analgesics to manage acute and chronic pain conditions. Within any given year during the past five, 15% of the U.S. population filled at least one opioid prescription. In 2012, 259 million opioid prescriptions were written in the U.S. ? enough for every American adult to have one bottle of opioid painkillers in their home medicine cabinet. In 2013, nearly two million Americans aged 12 or older either abused or were dependent on opioid painkillers. Opioid poisoning or overdose deaths have more than quadrupled from 4,030 in 1999 to 18,893 in 2014. Total prescription opioid overdose costs in the U.S. were more than $20 billion in 2009.This is a significant and rapidly growing problem. Solution: Venebio Opioid Advisor (VOA) is a clinical decision support system (CDSS) based on VG?s existing, patent-pending, risk-index algorithm that accurately identifies individuals at risk for overdose or serious opioid-induced respiratory depression (OIRD) by utilizing evidence-based clinical data gathered from patient electronic medical records (EMRs) as opioids are being prescribed. VOA will be delivered via a stand-alone computer application, embedded in an EMR system, or alternatively located on a remote server accessible through a secure Internet connection. VOA will extract a patient?s relevant clinical data automatically from the EMR, assess the patient?s risk for opioid overdose, and present the patient?s risk score directly to the health care provider ? enabling evidence-based guidance and education that is personalized to the individual patient's specific risk factor profile. The ability to identify individuals at elevated risk of experiencing prescription opioid-related toxicity or opioid overdose will provide awareness of the individual risk level to both the health care provider and the patient. Methods: The overarching objective of our proposed Phase II research is first to refine and validate the clinical content used to create the existing Venebio Opioid Advisor algorithm, then to incorporate this refined information, along with the additional, evidence-based guidance and educational content, into a clinical decision support system, and finally to validate this CDSS during a prospective pilot study of VOA in the real-world clinical pain management setting.